Certain viruses may, under some conditions, produce an acute disease, and under other conditions produce a chronic disease. Little is known about the mechanism involved in the acute vs. chronic disease potential of a virus. Mouse hepatitis virus (MHV) type 4 (JHM) produces an acute fatal encephalomyelitis or a chronic demyelinating disease. The overall objective of this work is to determine the virus-dependent and host-dependent factors affecting virus chronicity and persistence. Temperature-sensitive mutants of MHV will be isolated in order to ascertain their possible role in demyelination and chronic disease, as well as to elucidate the biological properties of this virus. Other virus variants including defective interfering virus and plaque variants will be isolated and their disease causing potentials will be evaluated. A possible relationship between H-2 type and susceptibility to acute vs. chronic disease will be evaluated. Other host-dependent factors that may affect the development of chronic disease include the role of antibody induced antigenic modulation, depletion of complement levels, susceptibility of macrophages to infection and the role of cellular immunity. The clarification of the mechanism of MHV induced disease will significantly contribute towards an understanding of virus persistence and pathobiology of associated diseases.